Synthetic alkyl-ether-lipid promotes TRPV2 channel trafficking trough PI3K/Akt-girdin axis in cancer cells and increases mammary tumour volume. (July 2021)

• Record Type: Journal Article
• Authors: Guéguinou, Maxime; Felix, Romain; Marionneau-Lambot, Séverine; Oullier, Thibauld; Penna, Aubin; Kouba, Sana; Gambade, Audrey; Fourbon, Yann; Ternant, David; Arnoult, Christophe; Simon, Gaëlle; Bouchet, Ana Maria; Chantôme, Aurélie; Harnois, Thomas; Haelters, Jean-Pierre; Jaffrès, Paul-Alain; Weber, Gunther; Bougnoux, Philippe; Carreaux, François; Mignen, Olivier; Vandier, Christophe; Potier-Cartereau, Marie
• Is Part Of: Cell calcium. Volume 97(2021)
• Publication Date: 2021-07
• Subjects: TRPV2 -- Constitutive Ca2+ entry -- Alkyl-ether-lipid -- Breast cancer cell migration; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2021.102435
• Languages: English
• ISSNs: 0143-4160

Abstract

Highlights: What is already known: Transient Receptor Potential Vanilloid type 2 (TRPV2) can be activated by lipids and is implicated in several cancers. Alkyl-ether-lipids have anti-tumour properties. What this study adds: Alkyl-ether-lipids modulate TRPV2 trafficking and cancer cells. What is the clinical significance? This study highlights the potential modulation of TRPV2 by alkyl-ether-lipids as a novel avenue for research in the treatment of metastatic cancer to directly target the primary tumour or to potentiate a chemotherapeutic agent. Abstract: The Transient Receptor Potential Vanilloid type 2 (TRPV2) channel is highly selective for Ca 2+ and can be activated by lipids, such as LysoPhosphatidylCholine (LPC). LPC analogues, such as the synthetic alkyl-ether-lipid edelfosine or the endogenous alkyl-ether-lipid Platelet Activating Factor (PAF), modulates ion channels in cancer cells. This opens the way to develop alkyl-ether-lipids for the modulation of TRPV2 in cancer. Here, we investigated the role of 2-Acetamido-2-Deoxy-l-O-Hexadecyl-rac-Glycero-3-PhosphatidylCholine (AD-HGPC), a new alkyl-ether-lipid (LPC analogue), on TRPV2 trafficking and its impact on Ca 2+ -dependent cell migration. The effect of AD-HGPC on the TRPV2 channel and tumour process was further investigated using calcium imaging and an in vivo mouse model. Using molecular and pharmacological approaches, we dissected the mechanism implicated in alkyl-ether-lipids sensitive TRPV2 trafficking. We found that TRPV2 promotes constitutive Ca 2+ entry, leading to migration of highly metastatic breast cancer cell lines through the PI3K/Akt-Girdin axis. AD-HGPC addresses the functional TRPV2 channel in the plasma membrane through Golgi stimulation and PI3K/Akt/Rac-dependent cytoskeletal reorganization, leading to constitutive Ca 2+ entry and breast cancer cell migration (without affecting the development of metastasis), in a mouse model. We describe, for the first time, the biological role of a new alkyl-ether-lipid on TRPV2 channel trafficking in breast cancer cells and highlight the potential modulation of TRPV2 by alkyl-ether-lipids as a novel avenue for research in the treatment of metastatic cancer. Graphical abstract: Hypothetical schema represent TRPV2 trafficking induced by AD-HGPC. AD-HGPC activates PI3K/Rac1 GTPases and the PI3K/Akt pathway and induces translocation of TRPV2 to the plasma membrane by Golgi vesicle transport. Image, graphical abstract